Members of the cdc2 family of protein kinases are known to have a pivotal role in the regulation of cell cycle in eukaryotes. The potential roles of neuronal-specific cdc2-like kinase in stabilizing the neurofilament seketon and in axonal morphogenesis through phosphorylation of neurofilament and tau are not well delineated. The main objectives of this project are to disrupt the genomic locus of neuronal cdc2-like kinase (cdk5) and generate mouse models to study the function of these kinases; and to overexpress cdk5 in neuronal cell lines and in vivo in mice. During the past year, we have successfully generated cdk5 knock-out mice. The life-span of the mice is greatly shortened and the brains of the Cdk5(-/-) mice lack cortical laminar structure and cerebellar foliation. The large neurons in the brain stem and in the spinal cord show chromatolytic changes with accumulation of neurofilament immunoreactivity. Cdk5 appears to be an important molecule for brain development and neuronal differentiation. The results suggest that cdk5 has critical roles in neuronal cytoskeleton structure and organization.